Hypercholesterolemic patients (HCs) have endothelial dysfunction that may contribute to their risk for premature atherosclerosis. Endothelin (ET), a peptide released by endothelial cells, may contribute to this process by activating smooth muscle cell mitogenesis and monocyte chemotaxis. Therefore, to determine whether ET activity is increased in HCs, we compared the vasoactive effects of intraarterial infusion of an ETalpha-receptor blocker (BQ-123; 100 nmol/min for 60 min), alone and in combination with an ETbeta-receptor blocker (BQ-788; 50 nmol/min for 60 min) in 7 HCs (total cholesterol <250 mg/dL) and in 12 normal volunteers (NVs). The response to exogenous ET-1 infusion (5 pmol/min for 60 min) was also assessed in both groups on a separate day. Drugs were infused into the brachial artery and forearm blood flow (FBF) was measured by strain-gauge plethysmography. BQ-123 caused a vasodilator response in HCs, with a peak increase in FBF from baseline of 43% (from 3 +/- 0.3 (mean +/- SEM) to 4.30 +/- 0.8 mL/min/dL; p<0.05). The addition of BQ-788 to BQ-123 produced a vasoconstrictor effect, with return of FBF to values (3.3 +/- 0.4) similar to baseline (P=0.20). In contrast, in NVs FBF was not significantly changed from baseline (2.9 +/- 0.2 mL/min/dL) during infusion of either BQ-123 alone (2.6 +/- 0.2 mL/min/dL; P=0.53) or in combination with BQ-788 (2.6 +/- 0.2 mL/min/dL; P=0.15). Infusion of exogenous ET-1 resulted in a similar decrease in FBF in HCs (37 +/- 4%) and NVs (35 +/- 5%) (P=0.83). These findings indicate that HCs have enhanced vascular activity of ET, acting on both vasoconstrictor ETalpha and vasodilator ETbeta receptors. Because vascular sensitivity to exogenous ET-1 is not altered in HCs, our results suggest that endothelial synthesis and release of ET is increased in the vessels of HCs and may thereby contribute to the pathophysiology of the atherosclerotic process.